3-arylquinazoline derivatives as selective estrogen receptor beta modulators

ABSTRACT

Novel quinazoline derivatives possessing activity as estrogen receptor beta (ERβ) modulators are provided which have the general formula I 
                         
wherein
         X is O or S;   A and B are each independently CR′″ or N;   R, R′ and R″ are each independently hydrogen, alkyl, benzyl, p-methoxybenzyl, allyl, or Si(R 4 ) 3 , wherein at least one of R, R′ and R″ is hydrogen;   R′″ is hydrogen, halogen, CF 3 , OR 5 , S(O) n R 6 , NR 7 R 8 , cycloalkyl or alkyl;   R 1 , R 2  and R 3  are each independently hydrogen, halogen, CF 3 , OR 5 , S(O) n R 6 , NR 7 R 8 , cycloalkyl or alkyl;   R 4  is a alkyl;   R 5 , R 6 , R 7  and R 8  in each functional group are each independently hydrogen, cycloalkyl or alkyl; and   n is an integer from 0 to 2.       
     In addition, a method is provided for preventing, inhibiting or treating the progression or onset of pathological conditions associated with the estrogen receptor and to pharmaceutical compositions containing such compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from provisional application Ser. No.60/364,561, filed Mar. 15, 2002, incorporated herein by reference in itsentirety.

FIELD OF THE INVENTION

The present invention relates to novel, substituted quinazolinecompounds and their derivatives, methods of using such compounds in thetreatment of estrogen receptor-associated conditions, such as bonedisorders, for example osteoporosis, and to pharmaceutical compositionscontaining such compounds.

BACKGROUND OF THE INVENTION

The estrogen hormone has a broad spectrum of effects on tissues in bothfemales and males. Many of these biological effects are positive,including maintenance of bone density, cardiovascular protection,central nervous system (CNS) function and the protection of organsystems from the effects of aging. However, in addition to its positiveeffects, estrogen also is a potent growth factor in the breast andendometrium that increases the risk of cancer.

Until recently, it was assumed that estrogen binds to a single estrogenreceptor (ER) in cells. However, a second estrogen receptor, ER beta(ERβ), has been identified and cloned, with the original ER beingrenamed ER alpha(ERα). Endocrinology 1998 139 4252-4263. ERβ and ERαshare about a 50% identity in the ligand-binding domain and only 20%homology in their amino-terminal transactivation domain. The differencein the identity of the two ER subtypes accounts for the fact that smallcompounds may demonstrate a higher affinity to bind to one subtype overthe other.

Further, ERβ and ERα are believed to have varied distributions andfunctions in different tissues. For example, in rats, ERβ is stronglyexpressed in brain, bone and vascular epithelium, but weakly expressedin uterus and breast, relative to ERα. Further, ERα knockout mice aresterile and exhibit little or no evidence of hormone responsiveness ofreproductive tissues. In contrast, ERβ knockout mice are fertile andexhibit normal development and function of breast and uterine tissue.These observations suggest that selectively targeting ERβ over ERα couldconfer beneficial effects in several important diseases, such asAlzheimer's disease, anxiety disorders, depressive disorders,osteoporosis and cardiovascular diseases, without the liability ofreproductive system side effects. Selective effects on ERβ expressingtissues over uterus and breast could be achieved by agents thatselectively interact with ERβ over ERα.

Accordingly, it would be advantageous to develop a series of novelcompounds, which selectively modulate ERβ receptors and may be employedto treat a variety of estrogen-dependent pathological conditions.

SUMMARY OF THE INVENTION

In accordance with the present invention, substituted quinazolinederivatives are provided which have the structure of formula I

wherein

-   -   X is oxygen (O) or sulfur (S);    -   A and B are each independently CR′″ or N;    -   R, R′ and R″ are each independently hydrogen, alkyl, benzyl,        p-methoxybenzyl, allyl, or Si(R₄)₃, wherein at least one of R,        R′ and R″ is hydrogen;    -   R′″ is hydrogen, halogen, CF₃, OR₅, S(O)_(n)R₆, NR₇R₈,        cycloalkyl or alkyl;    -   R₁, R₂ and R₃ are each independently hydrogen, halogen, CF₃,        OR₅, S(O)_(n)R₆, NR₇R₈, cycloalkyl or alkyl;    -   R₄ is alkyl:    -   R₅, R₆, R₇ and R₈ in each functional group are each        independently hydrogen, cycloalkyl or alkyl; and    -   n is an integer from 0 to 2.

The compounds of formula I above further include all pharmaceuticallyacceptable salts, stereoisomers and prodrug esters of formula I.

The compounds of formula I modulate the function of the estrogenreceptor beta (ERβ) and include compounds which are, for example,selective agonists, partial agonists, antagonists or partial antagonistsof the ERβ. Consequently, the compounds of the present invention may beused in the treatment of multiple diseases or disorders associated withERβ activity, such as the treatment of bone disorders, cardiovasculardiseases, hypercholesterolemia, hypertriglyceridemia, vasomotordisorders, urogenital disorders, prostatic hypertrophy, endometrialhyperplasia and cancer. Further, the compounds of the present inventionmay have central nervous system (CNS) action and therefore may be usefulfor the treatment of multiple CNS disorders, such as neurodegenerativediseases.

The present invention provides for compounds of formula I,pharmaceutical compositions employing such compounds and for methods ofusing such compounds. In particular, the present invention provides apharmaceutical composition comprising a therapeutically effective amountof a compound of formula I, alone or in combination with apharmaceutically acceptable carrier.

In addition, a method is provided for preventing, inhibiting or treatingthe onset of pathological conditions associated with the estrogenreceptor, such as defined above and hereinafter, wherein atherapeutically effective amount of a compound of formula I isadministered to a mammalian, i.e., human, patient in need of treatment.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore other agent(s).

Further, the present invention provides a method for preventing,inhibiting or treating the diseases as defined above and hereinafter,wherein a therapeutically effective amount of a combination of acompound of formula I and another compound of formula I and/or at leastone other type of therapeutic agent, is administered to a mammalian,i.e., human patient in need of treatment.

Preferred are compounds of formula I having the structure Ia:

wherein A, B, R′, R′″, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and n are asdescribed above.

Preferred compounds of formula I having structure Ia are those compoundswherein

-   a. R and R′ are hydrogen;-   b. R and R′ are hydrogen; and    -   R₁, R₂, R₃ are hydrogen, and-   b. R′ is hydrogen;    -   R₁ and R₂ are hydrogen; and    -   R₃ is fluoro, chloro or methyl.

Further embodiments of compounds of the invention include the following:

DETAILED DESCRIPTION OF THE INVENTION

The following abbreviations are employed herein:

-   DMAP=4-(dimethylamino)pyridine-   DMF=N,N-dimethylformamide-   EtOAc=ethyl acetate-   EtSNa=sodium ethylthiolate-   ESI=electron spray injection-   g=gram(s)-   HPLC=high performance liquid chromatography-   h or hr=hour(s)-   LC/MS=high performance liquid chromatography/mass spectrometry-   MeOH=methyl hydroxide-   M+H=parent plus a proton-   M−H=parent minus a proton-   mg=milligram(s)-   min=minute(s)-   mL=milliliter(s)-   mmol=millimole(s)-   mol=mole(s)-   MP=melting point-   MS or Mass Spec=mass spectrometry-   NaHMDS=sodium hexamethyldisilazane-   NMR=nuclear magnetic resonance-   RT=room temperature-   THF=tetrahydrofuran-   μL=microliter(s)

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instances.

The term “alkyl” or “alk” as employed herein, alone or as part ofanother group, includes both straight and branched chain hydrocarbons,containing 1 to 20 carbons, preferably 1 to 10 carbons, more preferably1 to 8 in the normal chain, such as methyl, ethyl, propyl, isopropyl,butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl,4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl,dodecyl, the various branched chain isomers thereof, and the like.“Substituted alkyl” includes an alkyl group optionally substituted withone or more functional groups which are attached commonly to suchchains, such as, but not limited to, halo, alkyl, alkoxy, aryl, aryloxy,aryl(aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkyloxy,optionally substituted amino, hydroxy, hydroxyalkyl, acyl, oxo,alkanoyl, heteroaryl, heteroaryloxy, cycloheteroalkyl, arylheteroaryl,arylalkoxycarbonyl, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl,aryloxyaryl, alkylamido, alkanoylamino, arylcarbonylamino, nitro, cyano,thiol, haloalkyl, trihaloalkyl, alkylthio and the like.

The term “cycloalkyl” means a cycloalkyl group preferably containing 3to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl. Any of such groups may be optionally substituted with one ormore substituents, such as, but not limited to any of the substituentsdescribed above for substituted alkyl.

As used herein, the term “benzyl” refers to CH₂C₆H₅.

The term “allyl” as used herein, refers to a —CH₂CH═CH₂.

As used herein, the term “halo” or “halogen” refers to fluorine,chlorine, bromine and iodine.

The term “modulator” refers to a chemical compound with capacity toeither enhance (e.g., “agonist” activity) or inhibit (e.g., “antagonist”activity) a functional property of biological activity or process (e.g.,enzyme activity or receptor binding); such enhancement or inhibition maybe contingent on the occurrence of a specific event, such as activationof a signal transduction pathway, and/or may be manifest only inparticular cell types.

The term “prodrug esters” as employed herein includes esters andcarbonates formed by reacting one or more hydroxyls of compounds offormula I with alkyl, alkoxy, or aryl substituted acylating agentsemploying procedures known to those skilled in the art to generateacetates, pivalates, methylcarbonates, benzoates and the like.

Any compound that can be converted in vivo to provide the bioactiveagent (i.e., the compound of formula I) is a prodrug within the scopeand spirit of the invention.

Various forms of prodrugs are well known in the art. A comprehensivedescription of prodrugs and prodrug derivatives are described in:

-   -   a.) The Practice of Medicinal Chemistry, Camille G. Wermuth et        al., Ch 31, (Academic Press, 1996);    -   b.) Design of Prodrugs, edited by H. Bundgaard, (Elsevier,        1985); and    -   c.) A Textbook of Drug Design and Development, P.        Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113-191        (Harwood Academic Publishers, 1991).        Said references are incorporated herein by reference.

An administration of a therapeutic agent of the invention includesadministration of a therapeutically effective amount of the agent of theinvention. The term “therapeutically effective amount” as used hereinrefers to an amount of a therapeutic agent to treat or prevent acondition treatable by administration of a composition of the invention.That amount is the amount sufficient to exhibit a detectable therapeuticor preventative or ameliorative effect. The effect may include, forexample, treatment or prevention of the conditions listed herein. Theprecise effective amount for a subject will depend upon the subject'ssize and health, the nature and extent of the condition being treated,recommendations of the treating physician, and the therapeutics orcombination of therapeutics selected for administration. Thus, it is notuseful to specify an exact effective amount in advance.

The compounds of formula I can be present as salts, which are alsowithin the scope of this invention. Pharmaceutically acceptable (i.e.,non-toxic, physiologically acceptable) salts are preferred. If thecompounds of formula I have, for example, at least one basic center,they can form acid addition salts. These are formed, for example, withstrong inorganic acids, such as mineral acids, for example sulfuricacid, phosphoric acid or a hydrohalic acid, with strong organiccarboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atomswhich are unsubstituted or substituted, for example acetic acid, such assaturated or unsaturated dicarboxylic acids, for example oxalic,malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, suchas hydroxycarboxylic acids, for example ascorbic, glycolic, lactic,malic, tartaric or citric acid, such as amino acids, (for exampleaspartic or glutamic acid or lysine or arginine), or benzoic acid, orwith organic sulfonic acids, such as (C₁-C₄) alkyl or arylsulfonic acidswhich are unsubstituted or substituted, for example by halogen, forexample methyl- or p-toluene-sulfonic acid. Corresponding acid additionsalts can also be formed having, if desired, an additionally presentbasic center.

Preferred salts of the compounds of formula I which contain a basicgroup include monohydrochloride, hydrogensulfate, methanesulfonate,phosphate or nitrate.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one of the R substituents.Consequently, compounds of formula I can exist in enantiomeric ordiastereomeric forms or in mixtures thereof. The processes forpreparation can utilize racemates, enantiomers or diastereomers asstarting materials. When diastereomeric or enantiomeric products areprepared, they can be separated by conventional methods, for example,chromatographic or fractional crystallization.

The compounds of the invention may be prepared as shown in the followingreaction schemes and description thereof, as well as relevant publishedliterature procedures available to those skilled in the art. Exemplaryreagents and procedures for these reactions appear hereinafter and inthe working Examples.

Reaction Scheme 1

The reaction of benzoxazinones compounds of formula II

-   -   in which    -   R₉ is hydrogen, CF₃, cycloalkyl or alkyl;    -   R₁₀ and R₁₁ are alkyl, benzyl or p-methoxybenzyl, allyl or        Si(R₄)₃;    -   R₄ is or alkyl,    -   R₁₂ is hydrogen, halogen, CF₃, OR₅, S(O)_(n)R₆, NR₇R₈,        cycloalkyl or alkyl;    -   R₅, R₆, R₇ and R₈ for each functional group are independently        hydrogen, cycloalkyl or alkyl; and    -   n is an integer from 0 to 2,        with the arylamino derivatives of formula III

-   -   where    -   A and B are independently CR′″ or N;    -   R₁₃ is hydrogen, halogen, CF₃, OR₅, S(O)_(n)R₆, NR₇R₈,        cycloalkyl or alkyl;    -   R₅, R₆, R₇ and R₈ for each functional group are hydrogen,        cycloalkyl or alkyl;    -   R′″ is hydrogen, halogen, CF₃, OR₅, S(O)_(n)R₆, NR₇R₈,        cycloalkyl or alkyl;    -   R₁₄ is alkyl, benzyl or p-methoxybenzyl, allyl or Si(R₄)₃;    -   R₄ is or alkyl; and    -   n is an integer from 0 to 2,        in excess of the arylamino compound, without any solvent or in        stoichiometric quantities of formula II in the presence of an        organic solvent such as toluene or xylene at a temperature of        between 20° and 180° C., will give the compounds of formula IVa

where A, B, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, are as defined above.

Compounds of formula I where A, B, R₂ and R₃ are as defined above, X═O;R₁ is hydrogen, CF₃, cycloalkyl or alkyl; and at least one of R, R′ andR″ is hydrogen, are obtained by the selective ether cleavage reactionsof compounds of general formula IVa by employing known procedures,depending on the nature of the protecting groups, generally known tothose skilled in the art (see, for example, T. W. Greene & P. G. M.Wuts, Protecting Groups in Organic Synthesis, 3^(rd) Edition, 1999[Wiley]).

Compounds of General Formula IVb

where A, B, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, are as defined above, areobtained from the reaction of compounds of general formula IVa with athiation reagent such as phosphorus pentasulfide (P₄S₁₀), or Lawesson'sreagent employing procedures generally known to those skilled in theart. (see, for example, Tetrahedron, 41, 5061 (1985); Org. Synth. Coll.Vol. 3, 332; 1955).

The same ether cleavage methods mentioned above can then be applied tothe compounds of general formula IVb to provide the compounds of formulaI where A, B, R, R′, R″, R′″, R₂ and R₃ are as defined above; X═S; R₁ ishydrogen, CF₃, cycloalkyl or alkyl. Alternatively, the same compoundscan be obtained directly by thiation of the compounds of general formulaI where A, B, R, R′, R″, R′″, R₂ and R₃ are as defined above; X═O; andR₁ is hydrogen, CF₃, cycloalkyl or alkyl, via one of the thiationmethods mentioned above.

The benzoxazinones compounds of formula II

where R₉, R₁₀, R₁₁ and R₁₂ are as defined above, can be obtained by thereaction of anthranilic acid derivatives of general formula V

where R₁₀, R₁₁ and R₁₂ are as defined above and R₁₅ is H or a alkyl,with orthoesters of general formula VI

where R₉ is as defined above and R₁₆ is hydrogen or alkyl.Alternatively, methods such as those described in J. HeterocyclicChemistry 36, 563, (1999), could be utilized to obtain compounds offormula II. The orthoesters of general formula VI are eithercommercially available or may be prepared according to methods generallyknown to those skilled in the art. (See, for example, the General Reviewon Properties of Orthoesters and their Use in Organic Synthesis,Mezheritskii, V. V.; Olekhnovich, E. P.; Dorofeenko, G. N.Nauchno-Issled. Inst. Fiz. Org. Khim., Rostov-on-Don, USSR Usp. Khim.(1973), 42(5), 896-940). Anthranilic acid derivatives of general formulaV are either commercially available or may be prepared according tomethods generally known to those skilled in the art. One convenientroute to prepare compounds of formula V is shown in reaction scheme 1.1below.

The commercially available aminoanisoles of general formula VII (ortheir acid salts)

where R₁₀, R₁₁, R₁₂ are as defined above, are reacted withoxalylchloride according to the known literature procedures (OrganicSynthesis Col. Vol. I p. 327.; Martinet J. Compt Rend 1918; 166:851; J.Org. Chem, 1969, 34 (11) 3484-91) to yield the 1H-indole-2,3-diones ofgeneral formula VIII where R₁₀, R₁₁, R₁₂ are as defined above.

The isatines of general formula VIII may then be subjected to anoxidation reaction, under basic conditions, by using H₂O₂/NaOH to yieldthe corresponding anthranilic acid of general formula V, where R₁₀, R₁₁,R₁₂ are as defined above and R₁₅ is H. Compounds of formula V were R₁₅isa alkyl can be obtained by the classical esterification methods as knownin the literature.

Reaction Scheme 2a and 2b

The reaction of compounds of general formula IX

-   -   where A, B, X, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are as defined above,        with the appropriate reagent selected from the compounds of        general formula VI

-   -   where R₉ and R₁₆ are as defined above, without any solvent, or        in the presence of an organic solvent at a temperature between        20° C. and 150° C., will provide, according to Scheme 2a, the        compounds of general formula IVa or IVb where A, B, R₉, R₁₀,        R₁₁, R₁₂, R₁₃, R₁₄, are as defined above.

Compounds of Formula IVa and IVb can be converted to the compounds offormula I where R₁ is hydrogen, CF₃, cycloalkyl or alkyl, as describedpreviously in reaction scheme 1.

Alternatively the reaction of compounds of general formula IX

-   -   where A, B, X, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are as defined above,        with the appropriate reagent selected from the compounds of        general formula X

-   -   where X′ is O or S; R₁₇ is hydrogen, halogen, CF₃, OR₅,        S(O)_(n)R₆, NR₇R₈, cycloalkyl or alkyl; R₅, R₆, R₇ and R₈ for        each functional group are each independently hydrogen,        cycloalkyl or a alkyl; and n is an integer from 0 to 2; without        any solvent, or in the presence of an organic solvent at a        temperature between 20° C. and 150° C., will give the compounds        of general formula XI where A, B, X, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄        are as defined above; R₁₈ is hydrogen, CF₃, OR₅, S(O)_(n)R₆,        NR₇R₈, cycloalkyl or alkyl; R₅, R₆, R₇ and R₈ for each        functional group are each independently hydrogen, cycloalkyl or        alkyl; and n is an integer from 0 to 2.

One can obtain compounds of general formula I where A, B, X, R, R′, R″,R′″, R₂ and R₃ are as defined above; R₁ is hydrogen, CF₃, OR₅,S(O)_(n)R₆, NR₇R₈, cycloalkyl or alkyl; R₅, R₆, R₇ and R₈ for eachfunctional group are each independently hydrogen, cycloalkyl or a alkyl;and n is an integer from 0 to 2, by the selective ether cleavagereactions of compounds of formula XI through various proceduresgenerally known in the art, depending on the nature of the protectinggroups, as previously described herein.

Compounds of general formula I where A, B, X, R, R′, R″, R′″, R₂ and R₃are as defined above and R₁ is a halogen, can be provided from compoundsof general formula XI, where R₁₈ is a halogen precursor, e.g., OH orNH₂, via various halogenation methods known in the literature.Halogenation is performed prior to the ether cleavage reaction describedabove.

One can obtain compounds of general formula IX where A, B, R₁₀, R₁₁, R₁₂R₁₃, R₁₄ are as defined above and X is O or S by the reaction of isatoicanhydrides of general formula XII

-   -   where R₁₀, R₁₁, R₁₂ are as defined above and X′ is O or S, with        arylamines of formula III

-   -   where A, B, R₁₃, R₁₄ are as defined above, in an organic        solvent, such as ethanol in the presence of an organic base,        (e.g., dimethylaminopyridine), at a temperature between 0° C.        and 190° C., according to Scheme 2.1 below.

Alternatively, compounds of general formula IX where A, B, R₁₀, R₁₁, R₁₂R₁₃, R₁₄ are as defined above and X is S can be obtained from thecorresponding compounds where X is O by the reaction of a thiationreagent, such as phosphorus pentasulfide (P₄S₁₀), or Lawesson's reagent,according to procedures generally known to those skilled in the art andas previously described herein.

Compounds of general formula XII where R₁₀, R₁₁, R₁₂ are as definedabove and X′ is O or S, may be prepared according to proceduresdescribed in the literature. For example, see Coppola, M., The Chemistryof Isatoic Anhydride Synthesis (1980), Vol. 7, 505-36; Wagner, G., Roth,L., Z. Chem. (1967) 7 339.

Reaction Scheme 3

The reaction of anthranilic acid derivatives of general formula V

where R₁₀, R₁₁, R₁₂ are as defined above and R₁₅ is hydrogen or a alkylgroup with an iso (thio) cyanate compound of general formula XIII

-   -   where R₁₃, R₁₄ are as defined above and X″ is O or S, without        any solvent or in an organic solvent, such as toluene, at a        temperature between 20° C. and 260° C., will give the compounds        of general formula XIV

-   -   where A, B, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ are as defined above and X″        is O or S.

Compounds of general formula XIV can be easily transformed to compoundsof formula I by the classical reactions of organic chemistry known toone skilled in the art, including alkylation, oxidation, reduction,halogenation, nucleophilic substitution, diazonium salt formation andhalogenation reactions according to the reaction Scheme 3 below.

For example, chlorination of the compounds of general formula XIV whereA, B, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, are as defined above and X″ is O, usingreagents like SOCl₂ or POCl₃ will provide the corresponding compounds ofgeneral formula XV.

These compounds can either be dehalogenated by hydrogenation orsubstituted by appropriate nucleophiles followed by an oxidationreaction to yield compounds of general formula XVI where A, B, R₁₀, R₁₁,R₁₂, R₁₃ and R₁₄ are as defined above; R₁₈ is hydrogen, OR₅, S(O)_(n)R₆,NR₇R₈, cycloalkyl or alkyl; R₅, R₆, R₇ and R₈ for each functional groupare each independently hydrogen, cycloalkyl or a alkyl; n is an integerfrom 0 to 2.

Compounds of formula XVI where R₁₈ is NH₂ can be further functionalizedby, for example, diazo salt formation and subsequent treatment bydifferent reagents according to known procedures in the literature toyield compounds of general formula XVII where A, B, R₁₀, R₁₁, R₁₂, R₁₃,R₁₄, are as defined above; R₁₉ is hydrogen, halogen, OR₅, S(O)_(n)R₆,NR₇R₈, cycloalkyl or alkyl; R₅, R₆, R₇ and R₈ for each functional groupare each independently hydrogen, cycloalkyl or a alkyl, n is an integerfrom 0 to 2.

Thiation followed by the ether cleavage or ether cleavage reaction ofthe compounds of general formula XVII will provide the compounds offormula I wherein

-   -   X is O or S;    -   A and B each independently are CR′″ or N;    -   R₁, R₂ and R₃ are each independently are hydrogen, halogen, CF₃,        OR₅, S(O)_(n)R₆, NR₇R₈, cycloalkyl or alkyl;    -   R, R′ and R″ are each independently hydrogen, alkyl, benzyl,        p-methoxybenzyl, an allyl or Si(R₄)₃,    -   R′″ is hydrogen, halogen, CF₃, OR₅, S(O)_(n)R₆, NR₇R₈,        cycloalkyl or alkyl;    -   R₄ is a alkyl    -   R₅, R₆, R₇ and R₈ for each functional group are each        independently hydrogen, cycloalkyl or a alkyl; and    -   n is an integer from 0 to 2.

Alternatively, in accordance with reaction scheme 4, one can obtain thecompounds of general formula XVIII where A, B, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄,are as defined above; and R₂₀ is OR₅, S(O)_(n)R₆, NR₇R₈, cycloalkyl oralkyl; R₅, R₆, R₇ and R₈ are each independently hydrogen, cycloalkyl ora alkyl; and n is an integer from 0 to 2, from the compounds of generalformula XIV, where A, B, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and X″ are as definedabove, by alkylation of formula XIV, followed by a nucleophilicdisplacement reaction, followed by oxidation. Subsequent thiation andether cleavage will provide the corresponding compounds of formula I.

One may obtain addition salts, particularly pharmaceutically acceptableaddition salts, from the compounds of formula I. For example, thecompounds of formula I may contain an acidic free phenol or thiol group,such as the salts of sodium, potassium and calcium. Alternatively, thecompounds of formula I may contain an amino group, such as an inorganicor organic acid, for example, hydrochloride, methanesulfonate, acetate,maleate, succinate, fumarate, sulfate, lactate or citrate.

Utility & Combinations

A. Utilities

The compounds of the present invention modulate the function of theestrogen receptor beta (ERβ), and include compounds which are, forexample, selective agonists, partial agonists, antagonists or partialantagonists of the ERβ. Thus, the present compounds are useful in thetreatment of a condition or disorder which can be treated by modulatingthe function or activity of an ERβ in a subject, wherein treatmentcomprises prevention, partial alleviation or cure of the condition ordisorder. Modulation may occur locally, for example, within certaintissues of the subject, or more extensively throughout a subject beingtreated for such a condition or disorder.

Accordingly, the compounds of the present invention can be administeredto mammals, preferably humans, for the treatment of a variety ofconditions and disorders, including, but not limited to bone disorders,e.g., osteoporosis (including glucocorticoid-induced osteoporosis),osteopenia, Paget's disease and peridontal disease; cardiovasculardiseases (including fibroproliferative conditions);hypercholesterolemia; hypertriglyceridemia; vasomotor disorders (e.g.,hot flashes); urogenital disorders (e.g., urinary incontinence);prostatic hypertrophy; endometrial hyperplasia; and cancer, includingprostate cancer, uterine cancer, ovarian cancer, breast cancer andendometrial cancer. Further, the compounds of the present invention mayhave central nervous system action and therefore may be useful for thetreatment of multiple CNS disorders, such as neurodegenerative diseases(e.g., improvement of cognitive function and the treatment of dementia,including Alzheimer's disease and short-term memory loss).

B. Combinations

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of formula I, alone orin combination with a pharmaceutical carrier or diluent. Optionally,compounds of the present invention can be used alone, in combinationwith other compounds of the invention, or in combination with one ormore other therapeutic agent(s) or other pharmaceutically activematerials.

For example, the compounds of the present invention may be employed incombination with other modulators of the estrogen receptor beta and/orwith other suitable therapeutic agents useful in the treatment of theaforementioned disorders, such as, but not limited to, anti-osteoporosisagents, cholesterol lowering agents, growth promoting agents, modulatorsof bone resorption and cardiovascular agents.

Examples of suitable anti-osteoporosis agents for use in combinationwith the compounds of the present invention include bisphosphonates(e.g., alendronate, risedronate, ibandronate and zolendrate),parathyroid hormone, PTH fragments and PTH analogues (e.g. PTH-(1-84)and PTH-(1-34)) and calcitonins.

Examples of suitable cholesterol lowering agents for use in combinationwith the compounds of the present invention include HMG-CoA reductaseinhibitors (e.g., pravastatin, lovastatin, atorvastatin, simvastatin,NK-104 (a.k.a. itavastatin, nisvastatin or nisbastatin) and ZD-4522(a.k.a. rosuvastatin, atavastatin or visastatin)), MTP inhibitors,fibrates (e.g., gemfibrozil) and bile acid sequestrants.

Examples of suitable growth promoting agents for use in combination withthe compounds of the present invention include growth hormonesecretagogues, such as GHRP-6, GHRP-1 (as described in U.S. Pat. No.4,411,890 and publications WO 89/07110 and WO 89/07111), GHRP-2 (asdescribed in WO 93/04081), NN703 (Novo Nordisk), LY444711 (Lilly),MK-677 (Merck), CP424391 (Pfizer) and B-HT920, or with growth hormonereleasing factor and its analogs or growth hormone and its analogs orsomatomedins including IGF-1 and IGF-2, or with alpha-adrenergicagonists, such as clonidine or serotinin 5-HT_(D) agonists, such assumatriptan, or agents which inhibit somatostatin or its release, suchas physostigmine and pyridostigmine.

Examples of suitable modulators of bone resorption for use incombination with the compounds of the present invention includeestrogen; selective estrogen receptor modulators (e.g., tamoxifen,lasofoxifene, TSE-424 and raloxifene); selective androgen receptormodulators, such as those disclosed in Edwards, Bio. Med. Chem. Let.,1999 9, 1003-1008 and J. Med. Chem., 1999 42, 210-212; hormonereplacement therapies; vitamin D and analogues thereof (e.g.,1,25-dihydroxy vitamin D3); elemental calcium and calcium supplements;cathepsin K inhibitors; chloride channel inhibitors (e.g., ClC-7inhibitors); MMP inhibitors; vitronectin receptor antagonists; Src SH₂antagonists; Src kinase inhibitors; vacular H⁺-ATPase inhibitors;osteoprotegrin; Tibolone; p38 inhibitors; prostanoids; PPAR gammaantagonists or isoflavinoids (e.g., genistein and ipriflavone);androgens (e.g., testosterone and dihydrotestosterone); RANK ligandantagonists; TRAP inhibitors; AP-1 inhibitors and progesterone receptoragonists (e.g., medroxyprogesterone acetate (MPA)).

Examples of suitable cardiovascular agents for use in combination withthe compounds of the present invention include vasopeptidase inhibitors,ACE inhibitors, α-reductase inhibitors, muscarinic Ach antagonists,acetylcholinesterase inhibitors, angiotensin II receptor antagonists,thrombin inhibitors, Factor Xa inhibitors, tissue plasminogenactivators, streptokinase, or other thrombolytic or antithromboticagents.

Compounds of formula I and their physiologically acceptable salts,prodrug esters or stereoisomers thereof may be formulated foradministration via any suitable means, for example, orally, such as inthe form of tablets, capsules, granules or powders; rectally, such as inthe form of suppositories; nasally, including administration to thenasal membranes, such as by inhalation spray; topically (includingbuccal and sublingual); vaginal or parental (including intramuscular,sub-cutaneous, intravenous, and directly into the affected tissue)administration or in a form suitable for administration by inhalation orinsufflation. The formulations may, where appropriate, be convenientlypresented in discrete dosage units and may be prepared by any of themethods well known in the art of pharmacy. All methods may include thestep of bringing into association the active compound with liquidcarriers or finely divided solid carriers, or both, and then ifnecessary, shaping the product into the desired formulation.

The active principle may be in the form of a solid or a liquid and canbe utilized in a composition such as tablet, capsule, ointment, solutionor suspension, or in other suitable carrier materials. Examples ofsuitable carrier materials are iontophoetic devices, rectalsuppositories, transdermal systems, granules, injectable preparations,or the like, prepared according to procedures known in the art. Further,the active principle comprising a pharmaceutically effective amount ofat least one compound of formula I, either alone or in combination, orin combination with one or more other active agent(s) may beincorporated with excipients normally employed in therapeutic medicines,such as talc, gum arabic, lactose, starch, magnesium stearate,polyuidone, cellulose derivatives, cacao butter, semisyntheticglycerides, aqueous or non-aqueous vehicles, fats of animal or vegetableorigin, glycols, various wetting agents, dispersants or emulsifiers,silicone gels, stabilizers, certain polymers or copolymers,preservatives, binders, flavorings, colors and the like, as called forby acceptable pharmaceutical practice.

Dosage of the active principle required for use in treatment may varynot only with the particular compound selected, but also with the routeof administration, the nature of the condition being treated and the ageand condition of the patient. In general, however, a suitable dose willbe in the range of from about 0.0002 to 300 mg/kg of body weight perday, particularly from about 0.02 to 50 mg/kg of body weight per day, ona regimen of single or 2 to 4 divided daily doses. For example, for anadult with an average weight of 60 to 70 Kg, the dosage of activeprinciple can vary between 1 and 500 mg when administered orally, in oneor more daily doses, or from 0.01 to 50 mg, when administeredparenterally in one or more daily dosages.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

The following examples serve to better illustrate, but not limit, someof the preferred embodiments of the invention.

EXAMPLE 1 4,6-dimethoxyindole-2,3-dione

12 g (63 mmol) of 3,5-dimethoxyaniline hydrochloride and 20 ml (230 mol)of oxalyl chloride were stirred at 165° C. for 30 min. The excess ofoxalyl chloride was distilled (the color of the reaction mixture changedfrom dark-red to green-yellow). The reaction mixture was cooled andmethanol was added. The resulting suspension was heated then filtered,washed with methanol and dried to yield 13 g of4,6-dimethoxyindole-2,3-dione (100% yield).

C₁₀H₉NO₄=207.19 g/mol; ESI-LC/MS (M+H)⁺=208; MP: 300-304° C; ¹H NMR (400MHz, DMSO-d₆): δ 10.9 (bs, 1H), 6.16 (d, J=1.76 Hz, 1H), 6.00 (d, J=1.76Hz, 1H), 3.91 (s, 3H), 3.88 (s, 3H).

EXAMPLE 2 4,6-dimethoxyanthranilic acid

To a heated mixture (in an oversized flask) of 13 g (63 mmol)4,6-dimethoxyindole-2,3-dione prepared in Example 1 and 108 ml of 33%NaOH solution was carefully added 20 ml of a 30% solution of H₂O₂. Avigorous exothermic reaction occurs. After all H₂O₂ was added, thereaction mixture was maintained at 100° C. for an additional 10 min. ThepH of the solution was brought to 8 with concentrated HCl and acidifiedto pH 5-6 with acetic acid. The solid was filtered, washed with waterand dried to yield 6.2 g of 4,6-dimethoxyanthranilic acid as a palebrown solid (50% yield).

C₉H₁₁NO₄=197.19 g/mol; HPLC purity=100%; ESI-LC/MS (M+H)⁺=198.: MP:120-125° C.; ¹H NMR (400 MHz, DMSO-d₆): δ 5.94 (d, J=1.76 Hz, 1H), 5.79(d, J=1.76 Hz, 1H), 3.75 (s, 3H), 3.71 (s, 3H).

EXAMPLE 3 Methyl 2-amino-4,6-dimethoxybenzoate

To a mixture of 0.627 g (3.18 mmol) of the 4,6-dimethoxy-anthranilicacid prepared in Example 2, 7 ml of MeOH, and 7 ml of THF, was added 8ml of trimethylsilyl-diazomethane. After standing overnight at roomtemperature, the mixture was concentrated to yield quantitatively thecorresponding methyl ester. The product was used without any furtherpurification in the following step.

C₁₀H₁₃NO₄=211.22 g/mol; HPLC purity=85%; ESI-LC/MS (M+H)⁺=212; ¹H NMR400 MHz, CDCl₃): δ 3.71 (s, 3H); 3.75 (s, 3H); 3.82 (s, 3H); 5.74 (d,1H); 5.78 (d, 1H).

EXAMPLE 4 5,7-dimethoxy-3,1-benzoxazine-4-one

A mixture of 1.0 g (5.07 mmol) of 4,6-dimethoxy-anthranilic acid, asprepared in Example 3, and 15 ml of triethylorthoformate (90.2 mmol) washeated to 140° C. for 4 h. The volatiles were evaporated under reducedpressure to give 0.8 g of 5,7-dimethoxy-3,1-benzoxazine-4-one as ayellow solid (76% yield), which was used without any furtherpurification.

C₁₀H₉NO₄=207.19 g/mol.

EXAMPLE 5 1,2-dihydro-5,7-dimethoxy-3,1-benzoxazine-2,4-dione(4,6-dimethoxyisatoic anhydride)

To a cooled (0° C.) brown solution of 4,6-dimethoxy anthranilic acid(76.0 g, 0.385 mol), prepared as in Example 2, in tetrahydrofuran (1.3L) was added triphosgene (40.0 g, 0.135 mol) in portions over a 20 minperiod. After 30 min, the reaction was warmed to room temperature andstirred for an additional 1.5 h. The reaction mixture was poured into anErlenmeyer flask containing water and cooled to 0° C. with an ice bath.Additional water was added to facilitate the stirring of the thick solidformed. After stirring for 30 min, the reaction mixture was filtered togive a beige solid. The solid was washed with water, air-dried, and thendried under high vacuum to give 79.2 g (92%) of the isatoic anhydride.

C₁₀H₉NO₅=223.18 g/mol; HPLC purity=>96%; ESI-LC/MS (M−H)⁻=221.9.: MP:287-293° C. decomposes; ¹H NMR (400 MHz, DMSO-d₆): δ 11.51 (bs, 1H),6.36 (d, J=1.76 Hz, 1H), 6.20 (d, J=1.76 Hz, 1H), 3.86 (s, 3H), 3.85 (s,3H).

EXAMPLE 6 5,7-dimethoxy-2-methyl-3,1-benzoxazine-4-one

The anthranilic acid (388 mg, 1.97 mmol) prepared in Example 2 was takenup in anhydrous methylene chloride (10 mL). Triethylamine (2.36 mmol)was added followed by addition of acetic anhydride (2.36 mmol). Thereaction mixture was heated at 40° C. for 18 hours. Subsequently, thereaction mixture was poured into water and extracted with methylenechloride. The organic layer was washed with saturated aqueous sodiumbicarbonate, brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo to afford5,7-dimethoxy-2-methyl-3,1-benzoxazine-4-one (51% yield).

C₁₁H₁₁NO₄=221.21 g/mol; HPLC purity=75%; ESI-LC/MS (M+H)⁺=222.07; ¹H NMR(400 MHz, DMSO-d₆): δ 6.58 (d, J=1.76 Hz, 1H), 6.46 (d, J=1.76 Hz, 1H),3.84 (s, 3H), 3.80 (s, 3H), 2.24 (s, 3H).

EXAMPLE 7 5,7-dimethoxy-2-ethyl-3,1-benzoxazine-4-one

To a mixture of anthranilic acid (207 mg, 1.05 mmol), as prepared inExample 2, and 3 mL anhydrous methylene chloride, was addedtriethylamine (2.73 mmol). The mixture was cooled to 0° C. Propionylchloride (2.52 mmol) was added dropwise to the reaction mixture. Thesolution was allowed to warm to ambient temperature over two hours. Thereaction mixture was quenched with water and extracted twice withmethylene chloride. The combined organic extracts were washed withbrine, dried over magnesium sulfate, filtered and concentrated in vacuoto afford 5,7-dimethoxy-2-ethyl-3,1-benzoxazine-4-one (83% yield).

C₁₂H₁₃NO₄=235.24 g/mol; HPLC purity=>99%; ESI-LC/MS (M+H)⁺=236.09. ¹HNMR (CDCl_(3,) 400 MHz): δ 1.33 (3H, t, J=7.5 Hz), 2.66 (2H, q, J=7.5Hz), 3.91 (3H, s), 3.97 (3H, s), 6.46 (1H, d, J=2.2 Hz), 6.61 (1H, d,J=2.2 Hz).

According to the method described in Example 7 and by using theappropriate acid chlorides, the following compounds of examples 8 to 11were prepared.

EXAMPLE 8 5,7-dimethoxy-2-n-propyl-3,1-benzoxazine-4-one

C₁₃H₁₅NO₄=249.26 g/mol; HPLC purity=90%; ESI-LC/MS (M+H)⁺=250.09; ¹H NMR(CDCl₃): δ 1.00 (3H, t, J=7.5 Hz), 1.83 (2H, m), 2.61 (2H, t, J=7.5 Hz),3.91 (3H, s), 3.96 (3H, s), 6.46 (1H, d, J=2.2 Hz), 6.61 (1H, d, J=2.2Hz).

EXAMPLE 9 5,7-dimethoxy-2-isopropyl-3,1-benzoxazine-4-one

C₁₃H₁₅NO₄=249.26 g/mol; HPLC purity=90%; ESI-LC/MS (M+H)⁺=250.08. ¹H NMR(CDCl_(3,) 400 MHz): δ 1.34 (6H, d, J=7.0 Hz), 2.87(1H, septet, J=7.0Hz), 3.91 (3H, s), 3.96 (3H, s), 6.46 (1H, d, J=2.2 Hz), 6.62 (1H, d,J=2.2 Hz)

EXAMPLE 10 5,7-dimethoxy-2-n-butyl-3,1-benzoxazine-4-one

C₁₄H₁₇NO₄=263.29 g/mol; HPLC purity=95%; ESI-LC/MS (M+H)⁺=264.4; ¹H NMR(CDCl₃): δ 0.95 (3H, t, J=7.3 Hz), 1.42 (2H, m) 1.78 (2H, m), 2.62 (2H,t, J=7.7 Hz), 3.91 (3H, s), 3.97 (3H, s), 6.46 (1H, d, J=2.2 Hz), 6.60(1H, d, J=2.2 Hz).

EXAMPLE 11 5,7-dimethoxy-2-isobutyl-3,1-benzoxazine-4-one

C₁₄H₁₇NO₄=263.29 g/mol; HPLC purity=94%; ESI-LC/MS (M+H)⁺=264.08; ¹H NMR(CDCl₃): δ 1.02 (6H, d, J=7.04 Hz), 2.29 (1H, m) 2.50 (2H, d, J=7.5 Hz),3.91 (3H, s), 3.97 (3H, s), 6.46 (1H, d, J=2.2 Hz), 6.63 (1H, d, J=2.2Hz).

EXAMPLE 12 Benzamide, 2-amino-4,6-dimethoxy-N-(4-methoxy-2-methylphenyl)

To a mixture of 150 mg (0.673 mmol) of the isatoic anhydride prepared inExample 5, 184 mg (1.34 mmol) of 4-methoxy-2-methylaniline and acatalytic amount of 4-dimethylaminopyridine (5 mg) at room temperaturewas added N,N-dimethylacetamide (1.5 mL). The mixture was heated at 110°C. under nitrogen atmosphere overnight, then cooled to room temperature.Solvent was removed in vacuo, and the residue was partitioned betweenEtOAc and water. The aqueous layer was extracted with EtOAc twice andthe combined organic layers were washed with water and brine, dried overNa₂SO₄, and concentrated. The residue was dissolved in CH₂Cl₂ containinga small amount of methanol and chromatographed on silica using 35% EtOAcin hexane as eluent. A total of 155 mg (72%) of a pink solid wasobtained.

C₁₇H₂₀N₂O₄=316 g/mol; HPLC purity=84%; ESI-LC/MS (M+H)⁺=317.

EXAMPLE 13 Benzamide, 2-amino-4,6-dimethoxy-N-(2-fluoro-4-methoxyphenyl)

To a mixture of 200 mg (1.42 mmol) of 4-amino-3-fluoroanisole and 1Msodium bis(trimethylsilyl)amide (4.39 mmol) in THF solution at roomtemperature under nitrogen atmosphere, 320 mg (1.42 mmol) of the isatoicanhydride prepared in Example 5, was added followed by the addition of 2mL of N,N-dimethylacetamide. The suspension was heated at 90° C. for 4hours. After completion of the reaction, as monitored by HPLC, themixture was cooled to room temperature, diluted with EtOAc and 1N HCl,and the resulting layers were separated. The aqueous layer was extractedwith EtOAc twice, and the combined organic extracts were washed withwater, saturated NaHCO₃, brine, dried over Na₂SO₄ and concentrated. Theresidue was dissolved in CH₂Cl₂ and chromatographed on silica using 30%EtOAc in hexane as eluent. A total of 220 mg (48%) of a yellow solid wasobtained.

C₁₆H₁₇FN₂O₄=320 g/mol; ESI-LC/MS (M+H)⁺=321.1; ¹H NMR (400 MHz, CDCl₃):δ 10.0 (1H, s), 8.26 (1H, t, J=8.8 Hz), 6.70 (2H, m), 6.42 (2H, broad),5.85 (1H, d, J=2.6 Hz), 5.82 (1H, d, J=2.6 Hz), 3.94 (3H, s), 3.79 (6H,s).

According to the procedures described in either Examples 12 or 13, andby the reaction of the appropriated anilines on the correspondingisatoic anhydrate, the following compounds in Examples 14 to 16 wereprepared.

EXAMPLE 14 Benzamide, 2-amino-4,6-dimethoxy-N-(3-fluoro-4-methoxyphenyl)

Used directly without any further purification by column chromatography.

C₁₆H₁₇FN₂O₄=320 g/mol; ESI-LC/MS (M+H)⁺=321.1.

EXAMPLE 15 Benzamide, 2-amino-4,6-dimethoxy-N-(3-chloro-4-hydroxyphenyl)

Purified by column chromatography, using 40% EtOAc in hexane as eluent.(52% yield).

C₁₅H₁₅ClN₂O₄=322 g/mol; ESI-LC/MS (M+H)⁺=323.1.

EXAMPLE 16 Benzamide, 2-amino-4,6-dimethoxy-N-(2-chloro-4-methoxyphenyl)

Purified by column chromatography using 30% EtOAc in hexane as eluent.(68% yield)

C₁₆H₁₇ClN₂O₄=336 g/mol; ESI-LC/MS (M+H)⁺=337.0.

EXAMPLE 175,7-dimethoxy-3-(4-methoxy-2-methylphenyl)-4(3H)-quinazolinone

A suspension of 150 mg (0.475 mmol) of the compound prepared in Example12 in triethylorthoformate (5 ml) was heated to reflux under N₂ for 5hours. HPLC showed reaction was complete. The solvent was removed invacuo to give a pink solid. The residue was dissolved in CH₂Cl₂ andchromatographed on silica using 70% EtOAc in hexane as eluent. A totalof 140 mg (90% yield) of5,7-dimethoxy-3-(4-methoxy-2-methylphenyl)-4(3H)-quinazolinone wasobtained as an off-white solid.

C₁₈H₁₈N₂O₄=326 g/mol; ESI-LC/MS (M+H)⁺=327.1; ¹H NMR (400 MHz, CDCl₃): δ7.90 (1H, s), 7.12 (1H, d, J=8.8 Hz), 6.87 (1H, d, J=2.6 Hz), 6.83 (1H,dd, J=2.6 Hz and J=8.8 Hz), 6.76 (1H, d, J=2.2 Hz), 6.51 (1H, d, J=2.2Hz), 3.94 (6H, s), 3.84 (3H,s) 2.1 (3H, s).

EXAMPLE 18 5,7-dimethoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinone

A mixture of 200 mg (0.97 mmol) of the benzoxazinone prepared in Example4 and 119 mg (0.97 mmol) of p-anisidine in 5 ml of xylene was refluxedfor 4 hours. The solvent was removed and the target compound purified byflash chromatography on silica gel (loaded with CH₂Cl₂ and eluted with40% EtOAc in hexane) to obtain 120 mg of5,7-dimethoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinone (40% yield) as awhite solid.

C₁₇H₁₆N₂O₄=312.33 g/mol; ESI-LC/MS (M+H)⁺=313; ¹H NMR (400 MHz,DMSO-d₆): δ 8.17 (1H, s), 7.36 (1H, d, J=8.8 Hz), 7.06 (1H, d, J=8.8Hz), 6.73 (1H, d, J=2.2 Hz), 6.61 (1H, d, J=2.2 Hz), 3.9 (s, 3H), 3.83(s, 3H), 3.82 (s, 3H).

EXAMPLE 19 5,7-dimethoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinone

A mixture of 50 g (0.224 mol) of the isatoic anhydride as prepared inExample 5, 68.9 g (0.560 mol) of p-anisidine, 2.73 g (0.022 mol) ofN,N-dimethylamino pyridine, and 500 mL of anhydrous dimethylacetamide,was warmed to 110° C. A clear brown solution formed at 80-90° C. andbubbling was observed (CO₂ loss). After 24 hr, the reaction was cooledto room temperature, diluted with water (1L), and extracted with EtOAc(3×500 mL). The combined organic layers were washed with brine (1×250mL), dried over MgSO₄, filtered, and concentrated to give a brownresidue weighing 85.2 g. The brown residue was dissolved in anhydroustriethylorthoformate (720 mL) and warmed to reflux for 4 hr. Uponcooling to room temperature, an off-white solid precipitated.Filtration, washing with triethylorthoformate (1×1 L), air drying, anddrying under high vacuum gave 55.1 g (79%) of5,7-dimethoxy-3-(4-methoxyphenyl)quinazoline-4-one, as an off-whitesolid.

C₁₇H₁₆N₂O₄=312.33 g/mol; HPLC purity=>98%; ESI-LC/MS (M+H)⁺=313.1; ¹HNMR (400 MHz, DMSO-d₆): δ 8.17 (s, 1H), 7.37 (d, 2H, J=8.8 Hz), 7.06 (d,2H, J=8.8 Hz), 6.73 (d, 1H, J=2.2 Hz), 6.62 (d, 1H, J=2.2 Hz), 3.9 (s,3H), 3.83 (s, 3H), 3.82 (s, 3H).

EXAMPLE 205,7-dimethoxy-2-methyl-3-(4-methoxyphenyl)-4(3H)-quinazolinone

To a mixture of 135.5 mg (0.612 mmol) of the benzoxazinone prepared inExample 6 and glacial acetic acid (2 mL), p-anisidine (0.735 mmol) wasadded and the reaction mixture was heated to 60° C. for 24 hrs. Thereaction mixture was concentrated in vacuo and partitioned between ethylacetate and saturated aqueous sodium bicarbonate. The organic layer waswashed with water, brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo to afford the product as a yellow oil (13.7%yield).

C₁₈H₁₈N₂O₄=326.36 g/mol; HPLC purity=>99%; ESI-LC/MS (M+H)⁺=327.0; ¹HNMR (CDCl₃): δ 2.19 (3H, s, methyl), 3.86 (3H, s), 3.90 (3H, s), 3.91(3H, s), 6.43 (1H, d, J=2.2 Hz), 6.68 (1H, d, J=2.2 Hz), 7.01 (2H, d,J=8.8 Hz), 7.13 (2H, d, J=8.8 Hz).

EXAMPLE 212-mercapto-5,7-dimethoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinone

The Example 3 compound (0.675 g, 3.19 mmol) was refluxed in 20 ml oftoluene with 0.525 g (3.2 mmol) of 4-methoxyphenylisothiocyanate for 15h. The solvent was evaporated and the residue triturated withMeOH/CH₂Cl₂ to yield 0.537 g of2-mercapto-5,7-dimethoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinone (49%)as an off-white solid.

C₁₇H₁₆N₂O₄S=344.39 g/mol; HPLC purity=91.7%; ESI-LC/MS (M+H)⁺=345.2; MP:322-326° C.; ¹H NMR (CDCl₃): δ 3.85 (3H, s), 3.9 (3H, s), 3.91 (3H, s),6.06 (1H, d, J=2.1 Hz), 6.08 (1H, d, J=2.1 Hz), 7.02 (1H, d, J=8.6 Hz),7.16 (2H, d, J=8.6 Hz), 9.38 (1H, s).

EXAMPLE 225,7-dimethoxy-3-(4-methoxyphenyl)-2,4(1H,3H)-quinazoline-dione

The previously prepared anthranilic acid from Example 2 (489 mg, 2.48mmol) was dissolved in 20 ml of anhydrous ethyl acetate and stirred over100 mg of 4 Å molecular sieves. 4-methoxybenzoic isocyanate (2.48 mmol)was added and the reaction mixture was heated to reflux for one hour.The reaction mixture was cooled to ambient temperature. Subsequently,the reaction mixture was filtered to remove the molecular sieves. Thesolvent was removed in vacuo to afford a mixture of uncyclized productand cyclized product. The crude mixture was taken up in ethanol andsaturated with hydrochloric acid. The reaction mixture was heated toreflux for two hours, then allowed to cool to ambient temperature. Theresulting mixture was purified by silica column (elution with 50% ethylacetate in hexanes) to afford the pure product (59% yield).

C₁₇H₁₆N₂O₅=328.32 g/mol; ESI-LC/MS (M+H)⁺=329.13; ESI-LC/MS (M−H)⁻327.07¹H NMR (DMSO-d₆): δ 3.78 (3H, s), 3.79 (3H, s), 3.83 (3H, s), 6.28 (1H,d, J=2.2 Hz), 6.31 (1H, d, J=2.2 Hz), 6.98 (2H, d, J=8.8 Hz), 7.12 (2H,d, J=8.8 Hz), 11.25 (1H, s).

According to any of the procedures described in Examples 17 to 22, andby reacting the appropriate amino compounds with the correspondingbenzamide, benzoxazinone, isatoic anhydride or anthranilic acidderivatives, the following compounds described in Examples 23 to 32 wereprepared.

EXAMPLE 233-(3-chloro-4-hydroxyphenyl)-5,7-dimethoxy-4(3H)-quinazolinone

C₁₇H₁₅ClN₂O₄=346 g/mol; HPLC purity=95.7%.

EXAMPLE 245,7-dimethoxy-3-(3-fluoro-4-methoxyphenyl)-4(3H)-quinazolinone

C₁₇H₁₅FN₂O₄=330 g/mol; HPLC purity=94%; ESI-LC/MS (M+H)⁺=331.1; ¹H NMR(400 MHz, CDCl₃): δ 8.00 (1H, s), 7.20 (1H, dd, J=11.4 Hz), 7.12−7.04(2H, m), 6.75 (1H, d, J=2.5 Hz), 6.51 (1H, d, J=2.2 Hz), 3.95 (6H, s),3.93 (3H, s).

EXAMPLE 25 5,7-dimethoxy-3-(6-methoxy-3-pyridinyl)-4(3H)-quinazolinone

C₁₆H₁₅N₃O₄=313 g/mol; HPLC purity=95%; ESI-LC/MS (M+H)⁺314; ¹H NMR(DMSO-d₆): δ 8.27 (1H, d, J=2.6 Hz), 8.23 (1H, s), 7.84 (1H, q, J=8.8 Hzand J=2.6 Hz), 6.97 (1H, d, J=8.8 Hz), 6.74 (1H, d, J=2.2 Hz), 6.63 (1H,d, J=2.2 Hz), 3.91 (3H, s), 3.90 (3H, s), 3.83 (3H, s).

EXAMPLE 265,7-dimethoxy-3-(3-fluoro-4-methoxyphenyl)-4(3H)-quinazolinone

C₁₇H₁₅FN₂O₄=330 g/mol; HPLC purity=100%; ESI-LC/MS (M+H)⁺=331.1; ¹H NMR(400 MHz, CDCl₃): δ 7.93 (1H, d, J=0.9 Hz), 7.27−7.25 (1H, m), 6.81−6.78(2H, m), 6.76 (1H, d, J=2.2 Hz), 6.51 (1H, d, J=2.2 Hz), 3.94 (3H, s),3.93 (3H, s), 3.86 (3H, s).

EXAMPLE 273-(3-chloro-4-methoxyphenyl)-5,7-dimethoxy-4(3H)-quinazolinone

C₁₇H₁₅ClN₂O₄ 346 g/mol; HPLC purity 95%; ESI-LC/MS (M+H)⁺=347.05; ¹H NMR(400 MHz, CDCl₃): δ 7.87 (1H, s), 7.30 (1H, d, J=8.8 Hz), 7.09 (1H, d,J=2.6 Hz), 6.93 (1H, dd, J=2.6 Hz and J=8.8 Hz), 6.77 (1H, d, J=2.6 Hz),6.51 (1H, d, J=2.2 Hz), 3.94 (6H, s), 3.86 (3H, s).

EXAMPLE 28 5,7-dimethoxy-2-ethyl-3-(4-methoxyphenol) quinazoline-4-one

C₁₉H₂₀N₂O₄=340.37 g/mol; HPLC purity=93%; ¹H NMR (CDCl₃): δ 1.18 (3H, t,J=7.4 Hz), 2.45 (2H, q, J=7.4 Hz), 3.86 (3H, s), 3.9 (3H, s), 3.93 (3H,s), 6.43 (1H, d, J=1.8 Hz), 6.79 (1H, d, J=1.8 Hz), 7.01 (2H, d, J=8.8Hz), 7.13 (2H, d, J=8.8 Hz).

EXAMPLE 29 5,7-dimethoxy-2-propyl-3-(4-methoxyphenol) quinazoline-4-one

C₂₀H₂₂N₂O₄=354.4 g/mol; HPLC purity=>99%; ESI-LC/MS (M+H)⁺=355.1. ¹H NMR(CDCl_(3,) 400 MHz): δ 0.92 (3H, t, J=7.5 Hz), 1.72 (2H, m), 2.86 (2H,t, J=7.9 Hz), 3.9 (3H, s), 3.94 (3H, s), 3.98 (3H, s), 6.56 (1H, d,J=2.2 Hz), 7.08 (2H, d, J=9 Hz), 7.17 (2H, d, J=9 Hz), 7.21 (1H, d,J=2.2 Hz).

EXAMPLE 30 5,7-dimethoxy-2-isopropyl-3-(4-methoxyphenol)quinazoline-4-one

C₂₀H₂₂N₂O₄ 354.4 g/mol; HPLC purity=90%; ¹H NMR (CDCl₃): δ 1.19 (6H, d,J=7 Hz), 2.70 (1H, septet, J=7 Hz), 3.86 (3H, s), 3.89 (3H, s), 3.93(3H, s), 6.41 (1H, d, J=2.2 Hz), 6.72 (1H, d, J=2.2 Hz), 7.00 (2H, d,J=8.8 Hz), 7.12 (2H, d, J=8.8 Hz).

EXAMPLE 31 5,7-dimethoxy-2-butyl-3-(4-methoxyphenol) quinazoline-4-one

C₂₁H₂₄N₂O₄=368.43 g/mol; HPLC purity=89%; ESI-LC/MS (M+H)⁺=369.11. ¹HNMR (CDCl_(3,) 400 MHz): δ 0.81 (3H, t, J=7.5 Hz), 1.25 (2H, m), 1.63(2H, m), 2.39 (2H, t, J=7.9 Hz), 3.86 (3H, S), 3.89 (3H, S), 3.92 (3H,S), 6.42 (1H, d, J=2.2 Hz), 6.71 (1H, d, J=2.2 Hz), 7.01 (2H, d, J=8.8Hz), 7.13 (2H, d, J=8.8 Hz).

EXAMPLE 32 5,7-dimethoxy-2-isobutyl-3-(4-methoxyphenol)quinazoline-4-one

C₂₁H₂₄N₂O₄=368.43 g/mol; purity (by NMR)=98%; ¹H NMR (CDCl₃): δ 0.92(6H, d, J=6.6 Hz), 2.03 (1H, m), 2.83 (2H, d, J=7.44 Hz), 3.89 (3H, s),3.94 (3H, s), 3.98 (3H, s), 6.56 (1H, d, J=1.8 Hz), 7.07 (2H, d, J=8.8Hz), 7.15 (2H, d, J=8.8 Hz), 7.30 (1H, d, J=1.8 Hz).

EXAMPLE 33 5,7-dimethoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinethione

The mixture of 5,7-dimethoxy-3-(4-methoxyphenyl)-quinazoline-4-one (240mg, 0.76 mmol), as prepared in Example 18 or 19, and Lawesson's reagent(310 mg, 0.76 mmol) in toluene (4 mL) was refluxed overnight. Themixture was evaporated to dryness. EtOAc was added and the mixture waswashed with water, brine and dried over MgSO₄. Evaporation gave a crudesolid. Purification was performed by flash chromatography on silica gel,loaded with dichloromethane and eluted with 45% ethyl acetate in hexane.The pure fraction was combined and evaporated to give a yellow foam (180mg, 72%).

C₁₇H₁₆N₂O₃S=328 g/mol; HPLC purity=95%; ESI-LC/MS (M+H)⁺=329; ¹H NMR(500 MHz, CDCl₃): δ 8.08 (1H, s), 7.20 (1H, d, J=8.8 Hz), 7.00 (1H, d,J=8.8 Hz), 6.71 (1H, d, J=2.2 Hz), 6.52 (1H, d, J=2.2 Hz), 3.9 (3H, s),3.83 (3H, s), 3.82 (3H, s).

EXAMPLE 345,7-dimethoxy-3-(4-methoxyphenyl)-2-(methylthio)-4(3H)-quinazolinone

A mixture of 171 mg (0.497 mmol) of the Example 21 compound, 15 ml ofMeOH, and 1 ml of 1N NaOH solution, was heated gently until a clearsolution was obtained. 295 mg (2 mmol) of methyl iodide was then addedand stirring was continued at room temperature for three days. Theprecipitate was filtered to yield 89.9 mg of5,7-dimethoxy-2-methylthio-3-(4-methoxyphenyl)-quinazoline-4-one as anoff-white solid (50% yield).

C₁₈H₁₈N₂O₄S=358.099 g/mol; HPLC purity=99%; ESI-LC/MS (M+H)⁺=358.9; MP:212-215° C.; ¹H NMR (CDCl₃): δ 2.49 (3H, s), 3.86 (3H, s), 3.9 (3H, s),3.92 (3H, s), 6.38 (1H, d, J=2.4 Hz), 6.64 (1H, d, J=2.4 Hz), 7.00 (1H,d, J=8.9 Hz), 7.17 (2H, d, J=8.9 Hz).

EXAMPLE 35 5,7-dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinone

To an ice-cooled mixture of 365 mg (1.17 mmol) of5,7-dimethoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinone, preparedaccording to the procedures described in Example 18 or 19, and 10 ml ofCH₂Cl₂, 3 ml of BBr₃ (31.7 mmol) was added. The mixture was stirred atroom temperature for 2 days. The solvent was evaporated, the obtainedresidue treated with a cold NaHCO₃ solution and extracted with EtOAc.The organic layer was washed with water and brine, dried over MgSO₄ andevaporated to yield a solid which purification by flash chromatographyon silica gel (loaded with CH₂Cl₂ and eluted with 66% EtOAc in hexane)gave 165 mg of 5,7-dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinone(40% yield) as a white solid.

C₁₄H₁₀N₂O₄=270.25 g/mol; HPLC purity=93.8%; ESI-LC/MS (M+H)⁺=271.1; MP:240-245° C.; ¹H NMR (CDCl₃): δ 6.46 (1H, d, J=2.2 Hz), 6.62 (1H, d,J=2.2 Hz), 7.0 (2H, d, J=8.8 Hz), 7.26 (2H, d, J=8.8 Hz), 8.09 (1H, s).

EXAMPLE 36 5,7-dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinone

A mixture of 100 mg (0.32 mmol) of5,7-dimethoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinone as prepared inExample 18 or 19, and 524 mg (6.24 mmol) of sodium ethanethiolate in 2ml of DMF was refluxed for 3.5 hr. DMF was evaporated and the residuedissolved in water. Concentrated HCl was added to adjust the pH to 5.The precipitate was filtered, dried and purified by chromatography onsilica gel (loaded with CH₂Cl₂ and a slight amount of MeOH, eluted with70% EtOAc in hexane) to yield 51 mg of5,7-dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinone (59%) as anoff-white solid.

This compound has the same characteristics as the compound of Example35.

EXAMPLE 37 5-hydroxy-7-methoxy-3-(4-methoxyphenyl)quinazoline4-one

A suspension of 5,7-dimethoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinone(2.40 g, 7.68 mmol), as prepared in Example 18 or 19 and anhydrouslithium chloride (6.51 g, 153.6 mmol) in anhydrous dimethylacetamide(51.2 mL) was warmed to 135° C. After 3 to 5 min the trimethoxy compoundgoes into solution, then after approximately 10 min a voluminousprecipitate formed. The precipitate redissolved after 20 min and theresulting solution was stirred at 135° C. for an additional 2.5 h. Uponcooling to room temperature, the reaction was poured into water (100 mL)and acidified with 1.0N HCl which gave a white precipitate. The mixturewas extracted with dichloromethane (3×). The combined organic layerswere washed with brine, dried over MgSO₄, filtered, and concentrated invacuo to remove the methylene chloride, leaving a white precipitate indimethylacetamide. Filtration provided 1.10 g (48% yield) of5-hydroxy-7-methoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinone, as a whitesolid.

C₁₆H₁₄N₂O₄=298.29 g/mol; HPLC purity 91%; ESI-LC/MS (M+H)⁺=299.1; ¹H NMR(400 MHz, DMSO-d₆): δ 11.77 (s, 1H), 8.26 (s, 1H) 7.48 (d, J=8.4 Hz,2H), 7.10 (d, J=8.8 Hz, 2H), 6.72 (d, J=2.2 Hz, 1H), 6.54 (d, J=1.3 Hz,1H), 3.88 (s, 3H), 3.83 (s, 3H).

According to the procedures described in Examples 35-37, the followingcompounds described in Example 38 and 39 were prepared.

EXAMPLE 38 5-hydroxy-3-(4-hydroxyphenyl)-7-methoxy-4(3H)-quinazolinone

C₁₅H₁₂N₂O₄=284.27 g/mol; HPLC purity=98.8%; ESI-LC/MS(M+H)⁺=(M+H)⁺=285.2, (M−H)⁻=283.0; ¹H NMR (DMSO-d₆): δ 11.2 (1H, s),9.95 (1H, s), 8.22 (1H, s), 7.38 (2H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8Hz), 6.72 (1H, d, J=2.4 Hz), 6.55 (1H, d, J=2.4 Hz), 3.90 (3H, s).

EXAMPLE 392-mercapto-5-hydroxy-3-(4-hydroxyphenyl)-7-methoxy-4(3H)-quinazolinone

C₁₅H₁₂N₂O₄S=316.05 g/mol; HPLC purity=97.5%; ESI-LC/MS (M+H)⁺=316.8.(M−H)⁻=314.8; MP: 325-328° C.; ¹H NMR (CD₃OD) δ 7.75 (1H, s), 7.03 (2H,d, J=9.1 Hz), 6.91 (2H, d, J=9.1 Hz), 6.28 (2H, s), 3.88 (3H, s).

EXAMPLE 40 5,7-dihydroxy-3-(4-hydroxyphenyl)quinazoline 4-one trisodiumsalt

15 mg (0.55 mmol) of the compound prepared in Example 35 or 36 wasdissolved in 1.65 ml of 1N NaOH solution while stirring for 30 min. Themixture was lyophilized to give the trisodium salt as a yellowish solid.

C₁₄H₇N₂Na₃O₄=336.19 g/mol; HPLC purity=94.2%; ESI-LC/MS (M+H)⁺=271; ¹HNMR (CD₃OD): δ 6.13 (1H, d, J=2.2 Hz), 6.31 (1H, d, J=2.2 Hz), 6.69 (2H,d, J=8.8 Hz), 6.99 (2H, d, J=8.8 Hz), 7.86 (1H, s).

EXAMPLE 41 5-ethoxy-7-methoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinone

To a suspension of5-hydroxy-7-methoxy-3-(4-methozyphenyl)-4(3H)-quinazolinone (0.015 g,0.0503 mmol), as prepared in Example 37, in dimethylformamide (0.26 mL)was added potassium carbonate (0.069 g, 0.503 mmol) and iodoethane(0.040 mL, 0.503 mmol). The reaction vessel was placed in a preheatedoil bath (120° C.) and after a few minutes the quinazolinone enters intosolution. After 3 h, the reaction was cooled to room temperature andexcess iodoethane was removed via rotary evaporation. The reactionmixture was diluted with water (0.75 mL) and extracted with EtOAc (3×).The combined organic layers were washed with brine (1×), dried overMgSO₄, filtered, and concentrated to give a yellow solid. Adsorptiononto silica gel (60 mg) and column chromatography (1:1 Hexane:EtOAc)provided 0.0080 g (49% yield) of5-ethoxy-7-methoxy-3-(4-methoxyphenyl)-4-(3H)-quinazolinone as a flakywhite solid.

C₁₈H₁₈N₂O₄=326.35 g/mol; ESI-LC/MS (M+H)⁺=327.2; ¹H NMR (400 MHz,CDCl₃): δ 8.0 (s, 1H), 7.29 (d, J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz, 2H),6.74 (d, J=2.6 Hz, 1H), 6.48 (d, J=2.6, 1H), 4.12 (q, J=7.0, 2H), 3.92(s, 3H), 3.85 (s, 3H), 1.52 (t, J=7.0 Hz, 3H).

EXAMPLE 42 5-ethoxy-7-hydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinone

To a solution of5-ethoxy-7-methoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinone (0.0080 g,0.0245 mmol), as prepared in Example 41, in dimethylformamide (0.25 mL),was added sodium ethanethiolate (0.0047 g, 0.0563 mmol). The resultingsuspension was warmed to 120° C. to form a solution. After each hour(for 7 hours) additional sodium ethanethiolate (0.0047, 0.0563 mmol) wasadded. After 7 hrs, the cloudy orange reaction solution was cooled toroom temperature and diluted with water (0.75 mL). The resulting yellowsolution was acidified with 1.0N HCl to pH 3 wherein the reactionsolution became cloudy. Extraction was performed with EtOAc (3×) anddichloromethane (3×). The combined organic layers were washed with brine(1×), dried over MgSO₄, filtered, and concentrated. Columnchromatography (5% MeOH in CH₂Cl₂) gave 0.0017 g (23%) of5-ethoxy-7-hydroxy-3-(4-hydroxyphenyl) quinazoline-4-one, as a whitesolid.

C₁₆H₁₄N₂O₄=298 g/mol; HPLC purity=>97%; ESI-LC/MS (M+H)⁺=299.1; ¹H NMR(400 MHz, CD₃OD) δ: 8.09 (s, 1H), 7.22 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.2Hz, 2H), 6.61 (d, J=2.2 Hz, 1H), 6.52 (d, J=2.2 Hz, 1H), 4.13 (q, J=7.0Hz, 2H), 1.44 (t, J=7.0 Hz, 3H).

EXAMPLE 437-benzyloxy-5-methoxy-3-(4-benzyloxyphenyl)-4(3H)-quinazolinone

To a cooled (0° C.) clear colorless solution of5,7-dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinone (0.330 g, 1.22mmol), as prepared in Example 35 or 36, in anhydrous dimethylacetamide(18.5 mL), was added sodium hydride (60% dispersion, 0.274 g, 6.85 mmol)portionwise over a 25 min. period. Following the final addition, thereaction mixture was stirred for an additional 30 minutes at 0° C. andthen warmed to room temperature for 1.5 h. Over the course of thereaction, the clear reaction solution became a clear, green color with awhite precipitate coating the sides of the reaction vessel. Uponrecooling to 0° C., benzyl bromide (0.29 mL, 2.44 mmol) was added. Thereaction was stirred at 0° C. for 1 hr. wherein the reaction solutionbecame a clear, orange solution. Next, iodomethane (0.14 mL, 2.22 mmol)was added. After 1 h at 0° C., the reaction was allowed to warm to roomtemperature and stir for 1 h. The reaction was diluted with water (45mL) and extracted with EtOAc (2×10 mL). The combined organic layers werewashed with brine (1×5 mL), dried over MgSO₄, filtered, and concentratedto give an orange residue. Column chromatography (1:1 hexane:EtOAc)provided 0.25 g (44%) of the product as a white foam.

C₂₉H₂₄N₂O₄=464.5 g/mol; HPLC purity=>95%; ESI-LC/MS (M+H)⁺=465.2; ¹H NMR(400 MHz, CDCl₃): δ 8.02 (s, 1H), 7.48-7.32 (m, 10H), 7.29 (d, J=9.2 Hz,2H), 7.07 (d, J=8.8 Hz, 2H) 6.83 (d, J=2.2 Hz, 1H), 6.59 (d, J=2.2 Hz,1H), 5.18 (s, 2H), 5.12 (s, 2H) 3.93 (s, 3H).

EXAMPLE 44 7-hydroxy-5-methoxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinone

To a solution of the Example 43 compound (0.200 g, 0.430 mmol) in 1:1EtOAc:ethanol (12.9 mL) was added 10% palladium on carbon (0.100 g).Hydrogen (balloon) was bubbled through the reaction for five minutes topurge the vessel and then the reaction was stirred vigorously under ahydrogen atmosphere for 4 h. The reaction was filtered through Celite®and the eluant was concentrated which gave a white solid weighing 0.122g. The crude material was adsorbed on silica gel (600 mg). Columnchromatography (7.5% MeOH in CH₂Cl₂) gave 0.015 g (12%) of a whitesolid.

C₁₅H₁₂N₂O₄=284 g/mol; HPLC purity=>95%; ESI-LC/MS (M+H)⁺=285.; MP:decomposes 240-360° C.; ¹H NMR (400 MHz, DMSO-d₆): δ 8.05 (s, 1H), 7.19(d, J=8.8 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 6.52 (s, 1H), 6.46 (s, 1H),3.78 (s, 3H).

EXAMPLE 45 5,7-Dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinethione

5,7-Dimethoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinethione (6.5 g, 19.8mmol), as prepared in Example 33, was dissolved in 75 ml of CH₂Cl₂. Thesolution was cooled to 0° C. and 37 ml of BBr₃ (396 mmol) was addeddropwise for 1 h 30 min. The reaction mixture was then stirred at roomtemperature until complete transformation of the starting material asmonitored by HPLC. The reaction mixture was evaporated to dryness. Acold saturated solution of NaHCO₃ was added and the resulting solidfiltered and dried. This solid was mixed with pyridine hydrochloridesalt (46 g, 396 mmol). The mixture was heated to 189° C. for 3.5 hours.Subsequently, the reaction was cooled to room temperature. Methanol wasadded to dissolve the mixture. The obtained dark solution was poured toa saturated NaHCO₃ solution and extracted with ethyl acetate. Thecombined organic phases were washed with brine and dried over MgSO₄ toyield a brownish solid that was purified by chromatography on silica gel(loaded with CH₂Cl₂ and a slight amount of MeOH, eluted with 2%, 2.5%,3% of MeOH in CH₂Cl₂) to provide5,7-dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinethione (3.4 g, 60%)as a yellow solid.

C₁₄H₁₀N₂O₃S=286 g/mol; HPLC purity =98.2%; ESI-LC/MS (M+H)⁺=287.; MP:299-302° C.; ¹H NMR (CD₃OD): δ 8.28 (1H, s), 7.18 (2H, d, J=8.8 Hz),6.93 (2H, d, J=8.8 Hz), 6.52 (1H, d, J=1.7 Hz), 6.42 (1H, d, J=1.7 Hz).

According to the procedures described in Examples 35-37 or 43-45, thefollowing compounds described in Examples 46 to 64 were prepared,starting from the appropriate ethers.

EXAMPLE 46 5,7-dihydroxy-3-(6-hydroxy-3-pyridinyl)-4(3H)-quinazolinone

Purified by preparative HPLC and obtained as an off-white solid.

C₁₃H₉N₃O₄=271 g/mol; HPLC purity=98%; ESI-LC/MS (M+H)⁺272.; MP: >360°C.; ¹H NMR (DMSO-D₆): δ 11.6 (1H, s), 10.7 (1H, s) 8.18 (1H, s), 7.77(1H, d, J=2.6 Hz), 7.59 (1H, q, J=2.6 Hz and J=9.7 Hz), 6.51 (1H, d,J=2.2 Hz), 6.42 (1H, d, J=9.7 Hz) 6.34 (1H, d, J=2.2 Hz).

EXAMPLE 475,7-dihydroxy-3-(4-hydroxyphenyl)-2-methyl-4(3H)-quinazolinone

C₁₅H₁₂N₂O₄=284.27 g/mol; purity (by NMR)=95%; ESI-LC/MS (M+H)⁺=285.04;ESI-LC/MS (M−H)⁻=283.02; ¹H NMR (CD₃OD): δ 2.17 (3H, s), 6.29 (1H, d,J=2.2 Hz), 6.47 (1H, d, J=2.2 Hz), 6.94 (2H, d, J=8.8 Hz), 7.14 (2H, d,J=8.8 Hz).

EXAMPLE 48 5,7-dihydroxy-2-ethyl-3-(4-hydroxyphenyl)-4(3H)-quinazolinone

C₁₆H₁₄N₂O₄=298.30 g/mol; HPLC purity=95%; ESI-LC/MS (M−H)⁻=297.17; ¹HNMR (CD₃OD): δ 1.07 (3H, t, J=7.5 Hz), 2.35 (2H, q, J=7.5 Hz), 6.20 (1H,d, J=2.2 Hz), 6.44 (1H, d, J=2.2 Hz), 6.85 (2H, d, J=8.8 Hz), 7.05 (2H,d, J=8.8 Hz).

EXAMPLE 495,7-dihydroxy-2-propyl-3-(4-hydroxyphenyl)-4(3H)-quinazolinone

C₁₇H₁₆N₂O₄=312. g/mol; HPLC purity=95%; ESI-LC/MS (M+H)⁺=313.1;ESI-LC/MS (M−H)⁻=311.0; ¹H NMR (CD₃OD): δ 0.77 (3H, t, J=7.46 Hz), 1.57(2H, m), 2.37 (2H, t, J=7.7 Hz), 6.24 (1H, d, J=2 Hz), 6.44 (1H, d, J=2Hz), 6.86 (2H, d, J=8.8 Hz), 7.07 (2H, d, J=8.8 Hz).

EXAMPLE 505,7-dihydroxy-2-isopropyl-3-(4-hydroxyphenyl)-4(3H)-quinazolinone

C₁₇H₁₆N₂O₄=312.33 g/mol; HPLC purity=96%; ESI-LC/MS (M+H)⁺=313.0;ESI-LC/MS (M−H)⁻=311.0; ¹H NMR (CD₃OD): δ 1.08 (6H, d, J=6.6 Hz), 2.61(1H, m) 6.08 (1H, d, J=2.2 Hz), 6.34 (1H, d, J=2.2 Hz), 6.83 (2H, d,J=8.8 Hz), 7.01 (2H, d, J=8.8 Hz).

EXAMPLE 51 5,7-dihydroxy-2-butyl-3-(4-hydroxyphenyl)-4(3H)-quinazolinone

C₁₈H₁₈N₂O₄: 326 g/mol; HPLC purity 99%; ESI-LC/MS (M+H)⁺=327.13;ESI-LC/MS (M−H)⁻=325.09; ¹H NMR (CD₃OD): δ 0.71 (3H, t, J=7.5 Hz), 1.14(2H, m), 1.50 (2H, m), 2.32 (2H, t, J=7.9 Hz), 6.19 (1H, d, J=2.2 Hz),6.41 (1H, d, J=2.2 Hz), 6.85 (2H, d, J=8.6 Hz), 7.05 (2H, d, J=8.6 Hz).

EXAMPLE 525,7-dihydroxy-2-isobutyl-3-(4-hydroxyphenyl)-4(3H)-quinazolinone

C₁₈H₁₈N₂O₄=326 g/mol; HPLC purity=96%; ESI-LC/MS (M+H)⁺=327.17;ESI-LC/MS (M−H)⁻=325.12; ¹H NMR (CD₃OD): δ 0.76 (6H, d, J=6.6 Hz), 1.94(1H, m) 2.24 (2H, d, J=7 Hz), 6.21 (1H, d, J=2.2 Hz), 6.43 (1H, d, J=2.2Hz), 6.85 (2H, d, J=8.8 Hz), 7.03 (2H, d, J=8.8 Hz).

EXAMPLE 53 5,7-dihydroxy-3-(4-hydroxyphenyl)-2,4(1l3H)-quinazolindione

C₁₄H₁₀N₂O₅=286 g/mol; HPLC purity=85%; ESI-LC/MS (M+H)⁺=287.02;ESI-LC/MS (M−H)⁻=284.99; ¹H NMR (CD₃OD): δ 5.98 (1H, d, J=2.2 Hz), 6.09(1H, d, J=2.2 Hz), 6.68 (2H, d, J=8.8 Hz), 7.33 (2H, d, J=8.8 Hz).

EXAMPLE 543-(3-chloro-4-hydroxyphenyl)-5,7-dihydroxy-4(3H)-quinazolinone

C₁₄H₉ClN₂O₄=304 g/mol; HPLC purity=96%; ESI/MS (M+H)⁺=304.8; ¹H NMR(DMSO-d₆): δ 11.7 (1H, s), 10.7 (1H, s), 8.18 (1H, s), 7.62 (1H, d,J=2.2 Hz), 7.30 (1H, d, J=8.8 Hz), 7.08 (1H, d, J=8.8 Hz), 6.52 (1H, d,J=1.8 Hz), 6,34 (1H, d, J=2.2 Hz).

EXAMPLE 555,7-dihydroxy-3-(3-fluoro-4-hydroxyphenyl)-4(3H)-quinazolinone

C₁₄H₉FN₂O₄=288 g/mol; HPLC purity=97%; ESI-LC/MS (M+H)⁺=288.9; ¹H NMR(DMSO-d₆): δ 11.7 (1H, s), 10.6 (1H, broad), 8.18 (1H, s), 7.47 (1H, dd,J=2.2 Hz and J=11.9 Hz), 7.18 (1H, d, J=8.8 Hz), 7.07 (1H, t, J=9 Hz),6.52 (1H, d, J=1.8 Hz), 6.34 (1H, d, J=2.2 Hz).

EXAMPLE 565,7-dihydroxy-3-(3-fluoro-4-hydroxyphenyl)-4(3H)-quinazolinone

C₁₄H₉FN₂O₄=288 g/mol; HPLC purity=99%; ESI-LC/MS (M+H)⁺288.8; ¹H NMR(DMSO-d₆): δ 11.5 (1H, s), 10.6 (1H, broad), 8.19 (1H, s), 7.44 (1H, t,J=8.8 Hz), 6.77 (2H, m), 6.54 (1H, d, J=2.2 Hz), 6.36 (1H, d, J=2.2 Hz).

EXAMPLE 573-(3-chloro-4-hydroxyphenyl)-5,7-dihydroxy-4(3H)-quinazolinone

C₁₄H₉ClN₂O₄=304 g/mol; HPLC purity=99%; ESI-LC/MS (M+H)⁺=304.8; ¹H NMR(DMSO-d₆): δ 11.5 (1H, s), 10.6 (1H, broad), 8.14 (1H, s), 7.49 (1H, d,J=8.4 Hz), 7.05 (1H, d, J=2.6 Hz), 6.90 (1H, dd, J=2.6 Hz and J=8.4 Hz),6.55 (1H, d, J=1.8 Hz), 6.36 (1H, d, J=2.2 Hz).

EXAMPLE 58 3-(4-hydroxyphenyl)-5,7-dihydroxy-2-mercapto-4(1,3H)-quinazolinone

C₁₄H₁₀N₂O₄S=302 g/mol; HPLC purity=89% MP=320-326° C.; ESI-LC/MS(M+H)⁺=303; ¹H NMR (400 MHz, CD₃OD): δ 7.01 (2H, d, J=8.8 Hz), 6.86 (2H,d, J=8.8 Hz), 6.16 (1H, d, J=1.9 Hz), 6.11 (1H, d, J=1.9 Hz).

EXAMPLE 595,7-dihydroxy-3-(4-hydroxy-2-methylphenyl)-4(3H)-quinazolinone

C₁₅H₁₂N₂O₄=284 g/mol; HPLC purity=99%; ESI-LC/MS (M+H)⁺=285.0; ¹H NMR(DMSO-d₆): δ 11.7 (1H, s), 10.7 (1H, s), 9.79 (1H, s), 8.09 (1H, s),7.20 (1H, d, J=8.4 Hz), 6.78 (1H, d, J=2.2 Hz), 6.72 (1H, dd, J=2.6 Hzand J=8.8 Hz ), 6.53 (1H, d, J=1.8 Hz), 6.34 (1H, d, J=2.2 Hz), 2.01(3H, s).

EXAMPLE 60 5,7-dihydroxy-3-(5-hydroxy-2-pyridyl)-4(3H)-quinazolinone

C₁₃H₉N₃O₄=271.06 g/mol; HPLC purity 97%; ESI-LC/MS (M+H)⁺=271.8;ESI-LC/MS (M−H)⁻=269.8; ¹H NMR (400 MHz, DMSO-d₆): δ 11.64 (1H, s),10.65 (1H, s), 8.3 (1H, s), 8.13 (1H, d, J=2.6 Hz), 7.59 (1H, d, J=8.4Hz), 7.4 (1H, q, J=2.6 Hz and 8.4 Hz), 6.56 (1H, d, J=1.8 Hz), 6.36 (1H,d, J=1.8 Hz).

EXAMPLE 61 5,7-dihydroxy-3-(4-hydroxy-3-methylphenyl)-4(3H)-quinazolinthione

C₁₅H₁₂N₂O₃S=300.8 g/mol; HPLC purity=99%; ESI-LC/MS (M+H)⁺=300.8ESI-LC/MS (M−H)⁻=298.8; ¹H NMR (400 MHz, DMSO-d₆): δ 13.52 (1H, s),11.03 (1H, s), 9.86 (1H, s), 8.34 (1H, s), 7.15 (1H, s), 7.07 (1H, d,J=8.8 Hz), 6.90 (1H, d, J=8.8 Hz), 6.58 (1H, d, J=1.8 Hz), 6.46 (1H, d,J=1.8 Hz), 2.15 (3H, s).

EXAMPLE 622-chloro-5,7-dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinone

C₁₄H₉ClN₂O₄=304.03 g/mol; HPLC purity=99%; ESI-LC/MS (M+H)⁺=304.9;ESI-LC/MS (M−H)⁻=302.96; ¹H NMR (CD₃OD): δ 7.16 (2H, m), 6.91 (2H, m),6.47 (1H, d, J=2.2 Hz), 6.35 (1H, d, J=2.2 Hz).

EXAMPLE 63 5,7-dihydroxy-3-(3-fluoro-4-hydroxyphenyl)-4(3H)-quinazolinthione

C₁₄H₉FN₂O₃S=304.3 g/mol; HPLC purity=99%; ESI-LC/MS (M+H)⁺=304.9ESI-LC/MS (M−H)⁻=302.8; ¹H NMR (500 MHz, DMSO-d₆): δ 13.43 (1H, s),11.06 (1H, s), 10.43 (1H, s), 8.37 (1H, s), 7.43 (1H, d, J=11.9 Hz),7.12 (2H, m), 6.58 (1H, d, J=2.3 Hz), 6.46 (1H, d, J=2.3 Hz).

EXAMPLE 645,7-dihydroxy-3-(4-hydroxy-3-methylphenyl)-4(3H)-quinazolinone

C₁₅H₁₂N₂O₄=284.27 g/mol; HPLC purity=99%; ESI-LC/MS (M+H)⁺=284.8ESI-LC/MS (M−H)⁻=282.9; ¹H NMR (400 MHz, DMSO-d₆): δ 11.78 (1H, s), 9.85(1H, s) 8.15 (1H, s), 7.22 (1H, s), 7.13 (1H, d, J=8.4 Hz), 6.90 (1H, d,J=8.8 Hz), 6.52 (1H, s), 6.34 (1H, s), 2.16 (3H, s).

1. A compound of the formula I

wherein X is O; A and B are each independently CR′″ or N, wherein A andB are each CR′″, or one of A and B is CR′″ and the of A and B is N; R isH; R′ is H; R₂ is H; R″ is selected from the group consisting ofhydrogen, alkyl, benzyl, p-methoxybenzyl, allyl and Si(R₄)₃; R′″ isselected from the group consisting of hydrogen, halogen, CF₃, OR₅,S(O)_(n)R₆, NR₇R₈, cycloalkyl and alkyl; R₁ and R₃ are eachindependently selected from the group consisting of hydrogen, halogen,CF₃, OR₅, S(O)_(n)R₆, NR₇R₈, cycloalkyl and alkyl, wherein alkyl isunsubstituted or is substituted with halo, alkyl, alkoxy, aryl, aryloxy,arylalkyl, arylalkyloxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkylalkyloxy, hydroxyl, hydroxyalkyl, acyl, oxo,alkanoyl, arylalkoxycarbonyl, aryloxyalkyl, aryloxyaryl, alkanoylamino,arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl oralkylthio; R₄ is a alkyl; R₅, R₆, R₇ and R₈ in each functional group areeach independently selected from the group consisting of hydrogen,cycloalkyl and alkyl; and n is an integer from 0 to 2, and prodrugesters and pharmaceutically acceptable salts thereof; wherein the term“prodrug esters” refers to esters and carbonates formed by reacting oneor more free hydroxyls, that is, where any of R, R′ and/or R″ is H, ofthe compound of formula I with alkyl, alkoxy, or aryl substitutedacylating agents.
 2. A compound having the structure Ia:

wherein X is O; A and B are each independently CR′″ or N, wherein A andB are each CR′″, or one of A and B is CR′″ and the other of A and B isN; R and R′ are each hydrogen; R₂ is hydrogen; R′″ is selected from thegroup consisting of hydrogen, halogen, CF₃, OR₅, S(O)_(n)R₆, NR₇R_(8,)cycloalkyl and alkyl; R₁ and R₃ are each independently selected from thegroup consisting of hydrogen, halogen, CF₃, OR₅, S(O)_(n)R₆, NR₇R₈,cycloalkyl and alkyl, wherein alkyl is unsubstituted or is substitutedwith halo, alkyl, alkoxy, aryl, aryloxy, arylalkyl, arylalkyloxy,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkylalkyloxy, hydroxyl, hydroxyalkyl, acyl, oxo, alkanoyl,arylalkoxycarbonyl, aryloxyalkyl, aryloxyaryl, alkanoylamino,arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl oralkylthio; R₄ is a alkyl; R₅, R₆, R₇ and R₈ in each functional group areeach independently selected from the group consisting of hydrogen,cycloalkyl and alkyl; n is an integer from 0 to 2; and prodrug estersand pharmaceutically acceptable salts thereof, wherein the term “prodrugesters” refers to esters and carbonates formed by reacting one or morefree hydroxyls, of the compound of formula Ia, with alkyl, alkoxy oraryl substituted acylating agents.
 3. The compound as defined in claim 2wherein R and R′ are hydrogen; and R₁, R₂, R₃ hydrogen.
 4. The compoundas defined in claim 2 wherein R₁ is hydrogen; and R₃ is fluoro, chloroor methyl.
 5. The compound as defined in claim 2 having the structure


6. A pharmaceutical composition comprising a compound as defined inclaim 1 and at least one additional therapeutic agent selected from thegroup consisting of other compounds of formula I, anti-osteoporosisagents, cholesterol lowering agents, growth promoting agents, modulatorsof bone resorption which are selected from estrogen, selective estrogenreceptor modulators, selective androgen receptor modulators; vitamin D;elemental calcium and calcium supplements; cathepsin_K inhibitors;chloride channel inhibitors; Src SH₂ antagonists; Src kinase inhibitors;vacular H⁺-ATPase inhibitors; osteoprotegrin; Tibolone; prostanoids;PPAR gamma antagonists or isoflavinoids; androgens; RANK ligandantagonists; AP-1 inhibitors and progesterone receptor agonists; andcardiovascular agents.
 7. The pharmaceutical composition as defined inclaim 6 wherein said cholesterol lowering agent is selected from thegroup consisting of pravastatin, lovastatin, simvastatin, atorvastatin,fluvastatin and cerivastatin.
 8. The pharmaceutical composition asdefined in claim 6 wherein said anti-osteoporosis agent is selected fromthe group consisting of bisphosphonates, parathyroid hormones, PTHfragments which are PTH-(1-84) and PTH-(1-34), and calcitonins.
 9. Amethod for treating osteoporosis, prostatic hypertrophy, endometrialhyperplasia or breast cancer, which comprises administrating to amammalian species in need of treatment a therapeutically effectiveamount of a compound as defined in claim
 1. 10. The method according toclaim 9 further comprising administering, concurrently or sequentially,a therapeutically effective amount of at least one additionaltherapeutic agent selected from the group consisting of other compoundsof formula I, anti-osteoporosis agents, cholesterol lowering agents,growth promoting agents, modulators of bone resorption which areselected from estrogen, selective estrogen receptor modulators,selective androgen receptor modulators; vitamin D; elemental calcium andcalcium supplements; cathepsin K inhibitors; chloride channelinhibitors; Src SH₂ antagonists; Src kinase inhibitors; vacularH⁺-ATPase inhibitors; osteoprotegrin; Tibolone; prostanoids; PPAR gammaantagonists or isoflavinoids; androgens; RANK ligand antagonists; AP-1inhibitors and progesterone receptor agonists; and cardiovascularagents.
 11. A method for treating osteoporosis which comprisesadministering to mammalian patient in need of treatment atherapeutically effective amount of a compound as defined in claim 1.12. The method according to claim 11 further comprising administering,concurrently or sequentially, a therapeutically effective amount of atleast one additional therapeutic agent selected from the groupconsisting of anti-osteoporosis agents, growth promoting agents andmodulators of bone resorption which are selected from estrogen,selective estrogen receptor modulators, estrogen, selective estrogenreceptor modulators, selective androgen receptor modulators; vitamin D;elemental calcium and calcium supplements; cathepsin K inhibitors;chloride channel inhibitors; Src SH₂ antagonists; Src kinase inhibitors;vacular H⁺-ATPase inhibitors; osteoprotegrin; Tibolone; prostanoids;PPAR gamma antagonists or isoflavinoids; androgens; RANK ligandantagonists; AP-1 inhibitors and progesterone receptor agonists.
 13. Apharmaceutical composition comprising a compound of formula I as definedin claim 1

wherein R is H; R′ is H; R₂ is H; X is O; A and B are each independentlyCR′″ or N, wherein A and B are each CR′″, or one of A and B is CR′″ andthe other of A and B is N; R″ is selected from the group consisting ofhydrogen, alkyl, benzyl, p-methoxybenzyl, allyl and Si(R₄)₃; R′″ isselected from the group consisting of hydrogen, halogen, CF₃, OR₅,S(O)_(n)R₆, NR₇R_(8,) cycloalkyl and alkyl; R₁ and R₃ are eachindependently selected from the group consisting of hydrogen, halogen,CF₃, OR₅, S(O)_(n)R₆, NR₇R₈, cycloalkyl and alkyl; R₄ is a alkyl: R₅,R₆, R₇ and R₈ in each functional group are each independently selectedfrom the group consisting of hydrogen, cycloalkyl and alkyl; and n is aninteger from 0 to 2, and prodrug esters and pharmaceutically acceptablesalts thereof; and a pharmaceutically acceptable carrier; wherein theterm “prodrug esters” refers to esters and carbonates formed by reactingone or more free hydroxyls, that is, where any of R, R′ and/or R″ is H,of the compound of formula I with alkyl, alkoxy or aryl substitutedacylating agents.
 14. A compound of the formula I

wherein X is S; A and B are each independently CR′″ or N, wherein A andB are each CR′″, or one of A and B is CR′″ and the other of A and B isN; R, R′ and R″ are each independently selected from the groupconsisting of hydrogen, alkyl, benzyl, p-methoxybenzyl, allyl andSi(R₄)₃, wherein at least one of R, R′ and R″ is hydrogen; R′″ isselected from the group consisting of hydrogen, halogen, CF₃, OR₅,S(O)_(n)R₆, NR₇R_(8,) cycloalkyl and alkyl; R₁, R₂ and R₃ are eachindependently selected from the group consisting of hydrogen, halogen,CF₃, OR₅, S(O)_(n)R₆, NR₇R₈, cycloalkyl and alkyl, wherein alkyl isunsubstituted or is substituted with halo, alkyl, alkoxy, aryl, aryloxy,arylalkyl, arylalkyloxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkylalkyloxy, hydroxyl, hydroxyalkyl, acyl, oxo,alkanoyl, arylalkoxycarbonyl, aryloxyalkyl, aryloxyaryl, alkanoylamino,arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl oralkylthio; R₄ is a alkyl; R₅, R₆, R₇ and R₈ in each functional group areeach independently selected from the group consisting of hydrogen,cycloalkyl and alkyl; and n is an integer from 0 to 2, and prodrugesters and pharmaceutically acceptable salts thereof; wherein the term“prodrug esters” refers to esters and carbonates formed by reacting oneor more free hydroxyls, that is, where any of R, R′ and/or R″ is H, ofthe compound of formula I with alkyl, alkoxy or aryl substitutedacylating agents.
 15. A compound having the structure Ia:

wherein X is S; A and B are each independently CR′″ or N, wherein A andB are each CR′″, or one of A and B is CR′″ and the other of A and B isN; R and R′ are each independently selected from the group consisting ofhydrogen, alkyl, benzyl, p-methoxybenzyl, allyl and Si(R₄)₃; R′″ isselected from the group consisting of hydrogen, halogen, CF₃, OR₅,S(O)_(n)R₆, NR₇R₈, cycloalkyl and alkyl; R₁, R₂ and R₃ are eachindependently selected from the group consisting of hydrogen, halogen,CF₃, OR₅, S(O)_(n)R₆, NR₇R₈, cycloalkyl and alkyl, wherein alkyl isunsubstituted or is substituted with halo, alkyl, alkoxy, aryl, aryloxy,arylalkyl, arylalkyloxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, cycloalkylalkyloxy, hydroxyl, hydroxyalkyl, acyl, oxo,alkanoyl, arylalkoxycarbonyl, aryloxyalkyl, aryloxyaryl, alkanoylamino,arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl oralkylthio; R₄ is alkyl; R₅, R₆, R₇ and R₈ in each functional group areeach independently selected from the group consisting of hydrogen,cycloalkyl and alkyl; n is an integer from 0 to 2; and prodrug estersand pharmaceutically acceptable salts thereof, wherein the term “prodrugesters” refers to esters and carbonates formed by reacting one or morefree hydroxyls, of the compound of formula Ia, with alkyl, alkoxy oraryl substituted acylating agents.
 16. The compound as defined in claim15 wherein R and R′ are hydrogen; and R₁, R₂, R₃ are hydrogen.
 17. Thecompound as defined in claim 15 having the structure


18. A pharmaceutically composition comprising a compound as defined inclaim 14 and a pharmaceutically acceptance carrier therefor.